Neuroscience Institute Cavalieri Ottolenghi

Orbassano, Italy

Neuroscience Institute Cavalieri Ottolenghi

Orbassano, Italy
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Tempia F.,University of Texas Medical Branch | Tempia F.,University of Turin | Tempia F.,Neuroscience Institute Cavalieri Ottolenghi | Tempia F.,National Institute of NeuroscienceTorino | And 7 more authors.
Frontiers in Cellular Neuroscience | Year: 2015

Genetically inherited mutations in the fibroblast growth factor 14 (FGF14) gene lead to spinocerebellar ataxia type27 (SCA27), an autosomal dominant disorder characterized by heterogeneous motor and cognitive impairments. Consistently, genetic deletion of Fgf14 in Fgf14−/− mice recapitulates salient features of the SCA27 human disease. In vitro molecular studies in cultured neurons indicate that the FGF14F145S SCA27 allele acts as a dominant negative mutant suppressing the FGF14 wild type function and resulting in inhibition of voltage-gated Na+ and Ca2+ channels. To gain insights in the cerebellar deficits in the animal model of the human disease, we applied whole-cell voltage-clamp in the acute cerebellar slice preparation to examine the properties of parallel fibers (PF) to Purkinje neuron synapses in Fgf14−/− mice and wild type littermates. We found that the AMPA receptor-mediated excitatory postsynaptic currents evoked by PF stimulation (PF-EPSCs) were significantly reduced in Fgf14−/− animals, while short-term plasticity, measured as paired- pulse facilitation (PPF), was enhanced. Measuring Sr2+-induced release of quanta from stimulated synapses, we found that the size of the PF-EPSCs was unchanged, ruling out a postsynaptic deficit. This phenotype was corroborated by decreased expression of VGLUT1, a specific presynaptic marker at PF-Purkinje neuron synapses. We next examined the mGluR1 receptor-induced response (mGluR1-EPSC) that under normal conditions requires a gradual build-up of glutamate concentration in the synaptic cleft, and found no changes in these responses in Fgf14−/− mice. These results provide evidence of a critical role of FGF14 in maintaining presynaptic function at PF-Purkinje neuron synapses highlighting critical target mechanisms to recapitulate the complexity of the SCA27 disease. © 2015 Tempia, Hoxha, Negro, Alshammari

Luzzati F.,University of Turin | Luzzati F.,Neuroscience Institute Cavalieri Ottolenghi | Fasolo A.,University of Turin | Peretto P.,University of Turin | Peretto P.,Neuroscience Institute Cavalieri Ottolenghi
Frontiers in Neuroscience | Year: 2011

Current advances in imaging techniques have extended the possibility of visualizing small structures within large volumes of both fixed and live specimens without sectioning. These techniques have contributed valuable information to study neuronal plasticity in the adult brain. However, technical limits still hamper the use of these approaches to investigate neurogenic regions located far from the ventricular surface such as parenchymal neurogenic niches, or the scattered neuroblasts induced by brain lesions. Here, we present a method to combine confocal laser scanning microscopy (CLSM) and serial section reconstruction in order to reconstruct large volumes of brain tissue at cellular resolution. In this method a series of thick sections are imaged with CLSM and the resulting stacks of images are registered and 3D reconstructed. This approach is based on existing freeware software and can be performed on ordinary laboratory personal computers. By using this technique we have investigated the morphology and spatial organization of a group of doublecortin (DCX)+ neuroblasts located in the lateral striatum of the late post-natal guinea pig. The 3D study unraveled a complex network of long and poorly ramified cell processes, often fascicled and mostly oriented along the internal capsule fiber bundles. These data support CLSM serial section reconstruction as a reliable alternative to the whole mount approaches to analyze cyto-architectural features of adult germinative niches. © 2011 Luzzati, Fasolo and Peretto.

Boda E.,University of Turin | Nato G.,University of Turin | Buffo A.,Neuroscience Institute Cavalieri Ottolenghi
Biochemical Pharmacology | Year: 2017

Neurodegenerative disorders are emerging as leading contributors to the global disease burden. While some drug-based approaches have been designed to limit or prevent neuronal loss following acute damage or chronic neurodegeneration, regeneration of functional neurons in the adult Central Nervous System (CNS) still remains an unmet need. In this context, the exploitation of endogenous cell sources has recently gained an unprecedented attention, thanks to the demonstration that, in some CNS regions or under specific circumstances, glial cells can activate spontaneous neurogenesis or can be instructed to produce neurons in the adult mammalian CNS parenchyma. This field of research has greatly advanced in the last years and identified interesting molecular and cellular mechanisms guiding the neurogenic activation/conversion of glia. In this review, we summarize the evolution of the research devoted to understand how resident glia can be directed to produce neurons. We paid particular attention to pharmacologically-relevant approaches exploiting the modulation of niche-associated factors and the application of selected small molecules. © 2017 Elsevier Inc.

Rolando C.,University of Turin | Rolando C.,Neuroscience Institute Cavalieri Ottolenghi | Parolisi R.,Neuroscience Institute Cavalieri Ottolenghi | Boda E.,University of Turin | And 6 more authors.
Journal of Neuroscience | Year: 2012

In the adult mammalian subventricular zone (SVZ), GFAP-positive neural stem cells (NSCs) generate neuroblasts that migrate tangentially along the rostral migratory stream (RMS) toward the olfactory bulb (OB). In the mouse brain, we found that the plasticity inhibitors Nogo-A and Nogo receptor 1 (NgR1) are differentially expressed in theSVZ-OBsystem, in which Nogo-A identifies immature neuroblasts and NgR1 germinal astrocytes. We therefore examined the role of Nogo-A and NgR1 in the regulation of neurogenesis. Pharmacological experiments show that Nogo-66/NgR1 interaction reduces the proliferation of NSCs. This is consistent with a negative-feedback loop, in which newly generated neurons modulate cell division of SVZ stem cells. Moreover, the Nogo-A-Δ20 domain promotes neuroblast migration toward the OB through activation of the Rho/ROCK (Rho-associated, coiled-coil containing protein kinase) pathway, without the participation of NgR1. Our findings reveal a new unprecedented function for Nogo-A and NgR1 in the homeostatic regulation of the pace of neurogenesis in the adult mouse SVZ and in the migration of neuroblasts along the RMS. © 2012 the authors.

Tomasi S.,University of Turin | Tomasi S.,Neuroscience Institute Cavalieri Ottolenghi | Caminiti R.,University of Rome La Sapienza | Innocenti G.M.,Karolinska Institutet
Cerebral Cortex | Year: 2012

Cortical areas differ in the size and distribution of neuronal cell bodies, density, and distribution of myelinated axons, connections, and functional properties. We find that they also differ in the diameter of long corticofugal axons, with the thickest axons originating from primary motor, somatosensory, and visual areas and the thinnest ones from prefrontal and temporal areas. Since diameter is proportional to axonal conduction velocity, it can be inferred that action potentials issued from the different areas will be relayed to their targets at different speed. Conduction delays also depend on conduction distance. By computing conduction velocity and conduction distances, we found the longest conduction delays for the primary visual and temporal areas and the shortest for the premotor, primary motor, and somatosensory areas, compatible with the available electrophysiological data. These findings seem to establish a new principle in cortical organization relevant to the pathophysiology of neurological or psychiatric illnesses as well as to the speed of information processing in cortical circuits. © 2011 The Author.

Lipp H.-P.,University of Zürich | Lipp H.-P.,University of KwaZulu - Natal | Bonfanti L.,University of Turin | Bonfanti L.,Neuroscience Institute Cavalieri Ottolenghi
Brain, Behavior and Evolution | Year: 2016

Mammalian adult neurogenesis has remained enigmatic. Two lines of research have emerged. One focuses on a potential repair mechanism in the human brain. The other aims at elucidating its functional role in the hippocampal formation, chiefly in cognitive processes; however, thus far it has been unsuccessful. Here, we try to recognize the sources of errors and conceptual confusion in comparative studies and neurobehavioral approaches with a focus on mice. Evolutionarily, mammalian adult neurogenesis appears as protracted juvenile neurogenesis originating from precursor cells in the secondary proliferation zones, from where newly formed cells migrate to target regions in the forebrain. This late developmental process is downregulated differentially in various brain structures depending on species and age. Adult neurogenesis declines substantially during early adulthood and persists at low levels into senescence. Short-lasting episodes in proliferation or reduction of adult neurogenesis may reflect a multitude of factors, and have been studied chiefly in mice and rats. Comparative studies face both species-specific variations in staining and technical abilities of laboratories, lacking quantification of important reference measures (e.g. granule cell number) and evaluation of maturational markers whose persistence might be functionally more relevant than proliferation rates. Likewise, the confusion about the functional role of variations in adult hippocampal neurogenesis has many causes. Prominent is an inferential statistical approach, usually with low statistical power. Interpretation is complicated by multiple theories about hippocampal function, often unrealistically extrapolating from humans to rodents. We believe that the field of mammalian adult neurogenesis needs more critical thinking, more sophisticated hypotheses, better statistical, technical and behavioral approaches, and a broader conceptual perspective incorporating comparative aspects rather than neglecting them. © 2016 S. Karger AG, Basel.

Grassi D.,Instituto Cajal | Grassi D.,University of Turin | Bellini M.J.,Instituto Cajal | Acaz-Fonseca E.,Instituto Cajal | And 3 more authors.
Endocrinology | Year: 2013

The expression of arginine-vasopressin (AVP) is regulated by estradiol and testosterone (T) in different neuronal populations by mechanisms that are not yet fully understood. Estrogen receptors (ERs) have been shown to participate in the regulation of AVP neurons by estradiol. In addition, there is evidence of the participation of ERβ in the regulation of AVP expression exerted by T via its metabolite 5α-dihydrotestosterone (5α-DHT) and its further conversion in the androgen metabolite and ERβ ligand 3β-diol. In this study we have explored the role of ERs in the regulation exerted by estradiol and T on AVP expression, using the human neuroblastoma cell line SH-SY5Y. Estradiol treatment increased AVP mRNA levels in SH-SY5Y cells in comparison with cells treated with vehicle. The stimulatory effect of estradiol on AVP expression was imitated by the ERα agonist 4,4′,4′,-(4-propyl- [1H]-pyrazole-1,3,5-triyl)trisphenol and blocked by the ER antagonist, ICI 182,780, and the ERα antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2- piperidinylethoxy)phenol]-1hpyrazoledihydrochloride. In contrast, the ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile reduced AVP expression, whereas the ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol enhanced the action of estradiol on AVP expression. T increased AVP expression in SH-SY5Y cells by a mechanism that was dependent on aromatase but not on 5α-reductase activity. The T effect was not affected by blocking the androgen receptor, was not imitated by the T metabolite 5α-DHT, and was blocked by the ERα antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol] -1hpyrazoledihydrochloride. In contrast, 5α-DHT had a similar effect as the ERβ agonists 2,3-bis(4-hydroxyphenyl)-propionitrile and 3β-diol, reducing AVP expression. These findings suggest that estradiol and T regulate AVP expression in SH-SY5Y cells through ERs, exerting a stimulatory action via ERα and an inhibitory action via ERβ. Copyright © 2013 by The Endocrine Society.

Parmigiani E.,University of Turin | Parmigiani E.,Neuroscience Institute Cavalieri Ottolenghi | Leto K.,University of Turin | Leto K.,Neuroscience Institute Cavalieri Ottolenghi | And 9 more authors.
Journal of Neuroscience | Year: 2015

Cerebellar GABAergic interneurons in mouse comprise multiple subsets of morphologically and neurochemically distinct phenotypes located at strategic nodes of cerebellar local circuits. These cells are produced by common progenitors deriving from the ventricular epithelium during embryogenesis and from the prospective white matter (PWM) during postnatal development. However, it is not clear whether these progenitors are also shared by other cerebellar lineages and whether germinative sites different from the PWM originate inhibitory interneurons. Indeed, the postnatal cerebellum hosts another germinal site along the Purkinje cell layer (PCL), in which Bergmann glia are generated up to first the postnatal weeks, which was proposed to be neurogenic. Both PCL and PWM comprise precursors displaying traits of juvenile astroglia and neural stem cell markers. First, we examine the proliferative and fate potential of these niches, showing that different proliferative dynamics regulate progenitor amplification at these sites. In addition, PCL and PWM differ in the generated progeny. GABAergic interneurons are produced exclusively by PWM astroglial-like progenitors, whereas PCL precursors produce only astrocytes. Finally, through in vitro, ex vivo, and in vivo clonal analyses we provide evidence that the postnatal PWM hosts a bipotent progenitor that gives rise to both interneurons and white matter astrocytes. © 2015 the authors.

Boido M.,Neuroscience Institute Cavalieri Ottolenghi | Garbossa D.,University of Turin | Fontanella M.,University of Turin | Ducati A.,University of Turin | Vercelli A.,Neuroscience Institute Cavalieri Ottolenghi
World Neurosurgery | Year: 2014

Background: Mesenchymal stem cells (MSCs) are multipotent stem cells that have a supportive role in regenerative therapies, especially in the central nervous system, where spontaneous regeneration is limited. MSCs can exert a paracrine activity and modulate the inflammatory response after a central nervous system injury. Spinal cord injury (SCI) leads to permanent neurologic deficits below the injury site, owing to neuronal and axonal damage. Among experimental treatments after SCI, cell transplantation has emerged as a promising approach. Methods: Using a compression injury model in the mouse spinal cord, MSCs were acutely transplanted into the lesion cavity; injured mice without the graft served as controls. After 26 days, the survival of MSCs was investigated, and their effect on the formation of glial cyst and on injury-related inflammation was evaluated. Results: Grafted MSCs remained permanently undifferentiated. The lesion volume was reduced by 31.6% compared with control mice despite the fact that astroglial and microglial activation was not altered by the graft. Sensory and motor tests showed that MSC cell therapy results in improvement on a battery of behavioral tests compared with control mice: MSC-treated mice versus control mice scored 0.00 versus 0.50 in the posture test, 0.00 versus 1.50 in the hindlimb flexion test, 3.00 versus 2.25 in the sensory test, and 7.50 mistakes versus 15.83 mistakes in the foot-fault test. Conclusions: These results underscore the therapeutic potential of MSCs, making them promising treatments for central nervous system pathologies. © 2014 Elsevier Inc.

Fontana R.,University of Milan | Fontana R.,Italian Institute of Technology | Della Torre S.,University of Milan | Meda C.,University of Milan | And 3 more authors.
Endocrinology | Year: 2014

Estrogens play an important role in the regulation of energy homeostasis in female mammals and a reduced ovarian function,dueto natural aging or surgery, is associated withbodyweight increase and fat redistribution. This disruption of energy homeostasis may constitute a trigger for several pathologiesknownto be associated with climacterium; however, so far, limited attention has been devoted to the ability of estrogen replacement therapies (ERT) to reinstate the balanced energy metabolism characteristic of cycling female mammals. The purpose of the present study was to compare the efficacy of selected ERTs in reversing the ovariectomy-induced gain in body weight. To this aim female ERE-Luc mice were ovariectomized and, after 3 weeks, treated per os for 21 days with: conjugated estrogens, two selective estrogen receptor modulators (bazedoxifene and raloxifene), and the combination of bazedoxifene plus conjugated estrogens (tissue-selective estrogen complex, TSEC). The study shows that the therapy based on TSEC was the most efficacious in reducing the body weight accrued by ovariectomy (OVX). In addition, by means of in vivo imaging, the TSEC treatment wasshownto increase estrogen receptor (ER) transcriptional activity selectively in the arcuate nucleus, which is a key area for the control of energy homeostasis. Finally, quantitative analysis of the mRNAs encoding orexigenic and anorexigenic peptides indicated that following ERT with TSEC there was a significant change in Agrp, NPY, and Kiss-1 mRNA accumulation in the whole hypothalamus. Considering that prior studies showed that ERT with TSEC was able to mimic the rhythm of ER oscillatory activity during the reproductive cycle and that such fluctuations were relevant for energy metabolism, the present observations further point to the ER tetradian oscillation as an important component of the ER signaling necessary for the full hormone action and therefore for an efficacious ERT. Copyright © 2014 by the Endocrine Society.

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